Project 4 Chronic stress during early postnatal life (ES) results in enduring deficits of learning and memory that become prominent during middle age. These cognitive impairments are associated with functional and structural derangements including profound loss of plasticity in select hippocampal CA3 and CAI synapses and impoverished apical dendritic trees. However, the molecular and cellular mechanisms by which ES persistently disrupts synapfic plasticity remain unresolved. ES persistently up-regulates the expression of the stress-acfivated neuropepfide CRH (corticotropin releasing hormone) in area CA3, and CRH destroys spines in the same dendritic domains that are structurally and funcfionally impaired after ES. These data suggest that CRH may be involved in the initial cascade of events provoked by ES, that eventually leads to synapfic dysfuncfion. Because seleefive derangements of synaptic plasficity and dendrite/spine integrity are shared among ES and several neurodevelopmental degenerative disorders discussed in this program, a converging, final mechanism for the effects of these disorders on synaptic function is plausible, and is supported by preliminary data. The aims of this project are to test the overarching hypothesis that initial molecular cascades unique to ES eventually converge onto a final common pathway involving deficits in the processes responsible for the reorganization and stabilization of dendritic spine actin-skeleton by patterned synaptic activity. We will (1) examine whether endogenous CRH mediates stress-induced spine dysfunction in middle aged hippocampus, and study the responsible molecular cascades; (2) test the role of CRH-receptor signaling in the abnormal spine function of ES rats; (3) examine the nature of ES-induced deficits in activity- dependent spine plasticity, and, finally, (4) use the concepts and information discussed above to assess the therapeutic potential of blocking hippocampal CRH receptors and / or enhancement of BDNF levels on synaptic plasticity and learning and memory function of middle-aged ES rats. Together, the proposed experiments will probe how ES, which correlates with later-life cognitive deficits in both humans and animal models, deranges hippocampal synapfic plasficity and spine integrity. The results will be used as foundation for mechanism-based therapeutic intervenfions aimed at ameliorating these memory deficits in animal models, setting the stage for translational efforts in humans. RELEVANCE (See instructions): Stress eariy in life leads to problems with learning and memory starting in middle age. This project studies the processes involved, focusing on the enduring effects ofthe stress on communication between brain cells, and on the integrity of cell elements that are affected in other disorders of learning and memory including mental retardation. Processes discovered in these studies will then be used to treat the deficits in cognitive funefion that are provoked by eariy-life stress, and may be applicable to other neurological diseases.